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Free access

Luigi Maione, Thierry Brue, Albert Beckers, Brigitte Delemer, Patrick Petrossians, Françoise Borson-Chazot, Olivier Chabre, Patrick François, Jérôme Bertherat, Christine Cortet-Rudelli, Philippe Chanson, and for the French Acromegaly Registry Group

Context

Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries.

Design

The French Registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 to 2012.

Results

Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI: 0.94–1.87) in men and 1.24 (0.77–1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70–1.42). Most deaths were due to cancer.

Conclusions

The majority of patients with acromegaly now have successful disease control thanks to the multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities.

Free access

Laurent Vroonen, Marie-Lise Jaffrain-Rea, Patrick Petrossians, Gianluca Tamagno, Philippe Chanson, Lucio Vilar, Françoise Borson-Chazot, Luciana A Naves, Thierry Brue, Blandine Gatta, Brigitte Delemer, Enrica Ciccarelli, Paolo Beck-Peccoz, Philippe Caron, Adrian F Daly, and Albert Beckers

Background

Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood.

Design and methods

A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly.

Results

Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CABmax/w) was 3.5 mg (2.0–10.5). Despite a higher CABmax/w in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CABmax/w (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CABmax/w or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%).

Conclusion

CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

Free access

Laurent Vroonen, Marie-Lise Jaffrain-Rea, Patrick Petrossians, Gianluca Tamagno, Philippe Chanson, Lucio Vilar, Françoise Borson-Chazot, Luciana A Naves, Thierry Brue, Blandine Gatta, Brigitte Delemer, Enrica Ciccarelli, Paolo Beck-Peccoz, Philippe Caron, Adrian F Daly, and Albert Beckers

Free access

Geneviève Sassolas, Zakia Hafdi-Nejjari, Laurent Remontet, Nadine Bossard, Aurélien Belot, Nicole Berger-Dutrieux, Myriam Decaussin-Petrucci, Claire Bournaud, Jean Louis Peix, Jacques Orgiazzi, Françoise Borson-Chazot, and the Group of Pathologists of the Rhône Alpes Region

Objective

The aim of the present study was to determine recent trends in thyroid cancer incidence rates and to analyze histopathological characteristics and geographical distribution.

Methods

Histologically proven 5367 cases were collected over the period 1998–2006 in France from the Rhône-Alpes thyroid cancer registry. Geographical variations of incidence were analyzed using a mixed Poisson model.

Results

The average incidence rates, age standardized to the world population, were 3.9/100 000 in men and 12.3/100 000 in women, higher than those previously reported in France. After an initial increase during the first 3 years, a steady level of incidence was observed for the period 2001–2006. The annual incidence rate of microcarcinomas was correlated with that of all cancers in men and women (r=0.78 and 0.89; P<0.01) respectively. Papillary microcarcinomas represented 38% of tumors and two-thirds of them measured less than 5 mm in diameter. They were fortuitously discovered after thyroidectomy for benign diseases in 64% of cases. Histological marks of aggressiveness differed according to the size of the tumor. Despite recent advances in diagnosis, 13% of tumors were diagnosed at advanced stage especially in men. Geographical distribution of incidence based on subregional administrative entities showed lower incidence rates in rural than in urban zones in men (relative rate: 0.72; 95% CI: 0.62–0.84) and women (relative rate: 0.85; 95% CI: 0.73–0.93).

Conclusion

The present study suggests that the rise in thyroid cancer incidence is now abating. It could reflect standardization in diagnostic procedures. Further studies, performed on a more prolonged period, are necessary to confirm these data.

Free access

Lucie Coppin, Margaux Dufosse, Pauline Romanet, Sophie Giraud, Marie-Odile North, Catherine Cardot Bauters, Françoise Borson-Chazot, Laurence Duchesne, Mélanie Métallo, Tonio Lovecchio, Anne Barlier, and Marie-Françoise Odou

Objective

Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73 = HRPT2 and CASR. During the last few years, new genes have been described as responsible for the development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease.

Design and methods

The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT).

Results

From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionally, the investigation of a large family showed that GCM2 variants could be associated with low penetrance.

Conclusion

We provide a description and interpretation for GCM2 variants identified in a French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of asymptomatic patients carrying such variants for calcemia.

Free access

Hélène Bihan, Arnaud Murat, Marinos Fysekidis, Abdallah Al-Salameh, Claire Schwartz, Eric Baudin, Philippe Thieblot, Françoise Borson-Chazot, Pierre-Jean Guillausseau, Catherine Cardot-Bauters, Isabelle Raingeard, Elisabeth Requeda, Jean Louis Sadoul, Yves Reznik, and Régis Cohen for the French Group of Endocrine Tumours (GTE)

Objective

Due to a strong genotype–phenotype correlation, the timing of prophylactic thyroidectomy in rearranged during transfection (RET) gene mutation carriers is usually dictated by genetic analysis.

Subjects and methods

We report a nationwide retrospective study of the clinical data of 77 French patients from 19 families with a mutation in codon 790 of the RET proto-oncogene.

Results

The average age at diagnosis was 35.6 years±20.5. Thirty-nine patients were women. Fifty-five patients underwent operations for the treatment of medullary thyroid carcinoma (MTC) at the mean age of 38 years (4–82 years). The mean follow-up duration was 89 months. TNM staging was as follows: T0NxMx in 19, TxNxMx in 1, T1NxMx in 22, T1N1Mx in 8, T2N1Mx in 1 and T3N1Mx in four patients. In the T1/x-Nx group, 96% were considered cured after surgery. In the N1 group (n=13), six patients had multifocal disease and five patients were cured. Age and gender were not significant predictors of remission. Twenty-two patients did not undergo an operation (age 1.5–78 years); among them, 11 patients had a mean basal calcitonin (CT) level of 9.8 pg/ml (2–24) after 53 months of follow-up. One patient had been operated on for phaeochromocytoma (PHEO), and their CT level remained normal for 262 months.

Conclusions

This study confirms that RET 790 mutation is associated with a non-aggressive form of multiple endocrine neoplasia type 2, as 28% of the patients were followed up without thyroidectomy, 25% had been thyroidectomised with no tumour being detected and even patients with MTC had slow-evolving disease. Moreover, only one patient had PHEO, and no-one had primary hyperparathyroidism.

Free access

Delphine Vezzosi, Catherine Cardot-Bauters, Nicolas Bouscaren, Maëlle Lebras, Mireille Bertholon-Grégoire, Patricia Niccoli, Nathalie Levy-Bohbot, Lionel Groussin, Philippe Bouchard, Antoine Tabarin, Philippe Chanson, Pierre Lecomte, Isabelle Guilhem, Nicolas Carrere, Eric Mirallié, François Pattou, Jean Louis Peix, Diane Goere, Françoise Borson-Chazot, Philippe Caron, Vanina Bongard, Bruno Carnaille, Pierre Goudet, and Eric Baudin

Objective

Management of insulinomas in the context of MEN1 remains poorly studied. The aim of this study was to evaluate long-term results of various surgical approaches in a large cohort of insulinoma–MEN1 patients.

Design and methods

Consecutive insulinoma–MEN1 patients operated on for a nonmetastatic insulinoma between 1957 and 2010 were retrospectively selected from the MEN1 database of the French Endocrine Tumor Group. The type of surgery was categorized as distal pancreatectomy (DP), total pancreatectomy/cephalic duodenopancreatectomy (TP/CDP), or enucleation (E). Primary endpoint was time until recurrence of hypoglycemia after initial surgery. Secondary endpoints were post-operative complications.

Results

The study included 73 patients (median age=28 years). Surgical procedures were DP (n=46), TP/CDP (n=9), or E (n=18). After a median post-operative follow-up of 9.0 years (inter-quartile range (IQR): 2.5–16.5 years), 60/73 patients (82.2%) remained hypoglycemia free. E and TP/CDP were associated with a higher risk of recurrent hypoglycemia episodes (unadjusted hazard ratio: 6.18 ((95% CI: 1.54–24.8); P=0.010) for E vs DP and 9.51 ((95% CI: 1.85–48.8); P=0.007) for TP/CDP vs DP. After adjustment for International Union against Cancer pTNM classification, enucleation remained significantly associated with a higher probability of recurrence. Long-term complications had occurred in 20 (43.5%) patients with DP, five (55.6%) with TP/CDP, but in none of the patients who have undergone E (P=0.002).

Conclusion

In the French Endocrine database, DP is associated with a lower risk for recurrent hypoglycemia episodes. Due to lower morbidity, E alone might be considered as an alternative.

Open access

Gudmundur Johannsson, Ulla Feldt-Rasmussen, Ida Holme Håkonsson, Henrik Biering, Patrice Rodien, Shigeyuki Tahara, Andrew Toogood, Michael Højby Rasmussen, and the REAL 2 Study Group

Objective

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin®. Local tolerability and treatment satisfaction were also assessed.

Design

26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939).

Methods

Male or female patients aged 18–79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan (n = 61) or once-daily Norditropin (n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).

Results

Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin (P = 0.0171).

Conclusions

In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin.

Free access

Joakim Crona, Eric Baudin, Massimo Terzolo, Alexandra Chrisoulidou, Anna Angelousi, Cristina L Ronchi, Cristina Lamas Oliveira, Els J M Nieveen van Dijkum, Filippo Ceccato, Françoise Borson-Chazot, Giuseppe Reimondo, Guido A M Tiberi, Hester Ettaieb, Andreas Kiriakopoulos, Letizia Canu, Darko Kastelan, Esthr Osher, Eugenia Yiannakopoulou, Giorgio Arnaldi, Guillaume Assié, Isabel Paiva, Isabelle Bourdeau, John Newell-Price, Karolina M Nowak, M Tous Romero, Maria Cristina De Martino, Maria João Bugalho, Mark Sherlock, Marie-Christine Vantyghem, Michael Conall Dennedy, Paula Loli, Patrice Rodien, Richard Feelders, Ronald de Krijger, Sam Van Slycke, Simon Aylwin, Valentina Morelli, Laurent Vroonen, Zulfiya Shafigullina, Irina Bancos, Małgorzata Trofimiuk-Müldner, Marcus Quinkler, Michaela Luconi, Matthias Kroiss, Mitsuhide Naruse, Peter Igaz, Radu Mihai, Silvia Della Casa, Alfredo Berruti, Martin Fassnacht, and Felix Beuschlein

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.